Photo by: geralt from Pixabay 2023

Dementia is the leading cause of death in the UK, yet it remains incurable and poorly treated. Alzheimer’s disease (AD), a subtype of dementia, is a devastating neurodegenerative disorder, characterised by progressive memory loss and cognitive decline, that gradually erodes independence. For decades, efforts to treat AD have focused on the amyloid cascade hypothesis, first introduced in 1992 by Sir John Hardy and Dr Gerald Higgins. This hypothesis suggests that the overproduction and accumulation of the protein, amyloid-beta (Aβ), are the central pathological hallmark and causative agent of AD. 

Despite huge investment in therapies aimed at reducing Aβ production and plaque formation, most have failed to deliver meaningful clinical benefit. This gap between pathological theory and therapeutic success has prompted scientists to explore alternative drivers of disease that may lead to more effective treatments.  

One key emerging driver is microglia, the brain’s resident immune cells.  

The term microglia was first coined in 1919 by Dr Pio del Rio-Hortega, translating from Greek to ‘small glue’. This name reflected the early view of microglia as passive support cells. We now know that this description significantly undermines their importance. Microglia are key coordinators of brain health homeostasis. They are best known for their phagocytic ability, ‘eating’ unwanted debris and pathological (disease-associated) proteins, including amyloid. Far from passive bystanders, microglia are highly dynamic cells, constantly surveying the brain’s environment to protect neurons. 

So why are microglia now emerging as key contributors to AD despite being fundamental to neuronal health?  

Prolonged exposure to Aβ can lead to the persistent activation of microglia. Rather than protecting neurons, they shift toward pro-inflammatory phenotypes, distinct toxic states that release inflammatory cytokines, driving neuronal damage via sustained neuroinflammation. Large-scale studies, such as the Human Microglia Atlas (HuMicA) developed by the Josep Carreras Leukaemia Research Institute, have identified distinct disease-associated subpopulations of microglia in AD patients, alongside elevated expression of genes associated with neuroinflammation.  

Crucially, these microglial phenotype shifts do not simply promote neuroinflammation but also alter key functions. In AD, microglia can excessively prune synapses, ‘eating’ junctions that allow neurons to communicate. By eliminating these synapses, microglia directly exacerbate AD pathology and contribute to memory loss. At the same time, these overactive microglia lose the capacity to perform their key protective function, becoming less effective at clearing surrounding Aβ aggregates, allowing amyloid to accumulate in the brain.  

Microglia are now recognised as key drivers of AD progression, promoting neuroinflammation, removing essential synapses, and limiting amyloid clearance. Targeting microglia in AD, therefore, presents a significant challenge: therapies must reduce harmful inflammation while also restoring their protective function. 

After decades of limited progress, therapeutic advancements are beginning to emerge. Recently FDA-approved monoclonal antibodies, donanemab and lecanemab, work by binding to amyloid plaques and promoting microglial clearance. Beyond this, researchers are now exploring different ways to directly reprogram neurotoxic microglia into protective phenotypes. Modulation of the microglial surface receptor TREM2, a key driver of protective phenotypic transitions, poses as a promising approach to restore microglial function and homeostasis. This avenue of treatment may offer a more holistic approach for treating this evidently complex disease. By enhancing amyloid clearance while simultaneously alleviating neuroinflammation and excessive synaptic pruning, microglial-targeted therapies may deliver clinical benefits beyond what amyloid-centric strategies can achieve in isolation. 

Microglia are an exciting and emerging target, offering a novel opportunity to slow cognitive decline and improve the quality of life of those affected by Alzheimer’s disease. 

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Article written by Summer Christian, an MBiol Neuroscience student at The University of Leeds.

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Article edited by Priscilla Wong, a Fourth-Year Biological Sciences (Immunology) student at the University of Edinburgh, and an Online News Editor for EUSci.

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References:

Alzheimer’s Research UK. 2024. Deaths due to dementia – Dementia Statistics Hub. Available from: https://dementiastatistics.org/about-dementia/deaths/.

Anwar, M.M., Pérez-Martínez, L. and Pedraza-Alva, G. 2024. Exploring the Significance of Microglial Phenotypes and Morphological Diversity in Neuroinflammation and Neurodegenerative Diseases: From Mechanisms to Potential Therapeutic Targets. Immunological Investigations. 53(6), pp.891–946.

Hardy, J.A. and Higgins, G.A. 1992. Alzheimer’s disease: The amyloid cascade hypothesis. Science. 256(5054), pp.184–185.

Martins-Ferreira, R., Calafell-Segura, J., Leal, B., Rodríguez-Ubreva, J., Martínez-Saez, E., Mereu, E., Pinho E Costa, P., Laguna, A. and Ballestar, E. 2025. The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditions. Nature communications. 16(1).

Smith, J.A., Das, A., Ray, S.K. and Banik, N.L. 2011. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain research bulletin. 87(1), p.10.

Valiukas, Z., Tangalakis, K., Apostolopoulos, V. and Feehan, J. 2025. Microglial activation states and their implications for Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease. 12(1), p.100013.